Assessment of Cancer Therapy Evaluation Program Advocacy and Inclusion Rates of People Living With HIV in Anti–PD1/PDL1 Clinical Trials

Key Points Question Has inclusion of people living with HIV in anti–programmed death 1 and anti–programmed death ligand 1 (anti–PD1/PDL1) immunotherapy trials changed during ongoing Cancer Therapy Evaluation Program advocacy efforts by the National Cancer Institute? Findings In this quality improvement analysis of 87 anti–PD1/PDL1 trials approved by the Cancer Therapy Evaluation Program from January 2014 to May 2019, the proportion of studies including people living with HIV increased from 16% of letters of intent to 70% of approved protocols. Inclusion of people living with HIV on submitted letters of intent increased over time. Meaning This study’s findings suggest that the increasing inclusion rates of people living with HIV in anti–PD1/PDL1 clinical trials are encouraging and that advocacy for these and other underrepresented populations should continue.


Introduction
The advent of highly active antiretroviral therapy (ART) has revolutionized the treatment of people living with HIV (PLWH), with many expected to have a nearly normal life expectancy. 1 Furthermore, the proportion of PLWH in the US aged 65 years or older is projected to increase from 8.5% in 2010 to 21.4% by 2030. 2 Cancer is now a leading cause of morbidity and mortality in this population, 3 with non-AIDS-defining cancers, such as lung and colon cancer, becoming increasingly prevalent. 2,4 In the past decade, the advent of anti-programmed death 1 and anti-programmed death ligand 1 (anti-PD1/PDL1) immune checkpoint blockade (ICB) has transformed the treatment of multiple malignant neoplasms. However, PLWH have routinely been excluded from ICB clinical trials. 5,6 Although a small number of studies focus exclusively on PLWH, the development of such trials begins a median (range) of 6.3 (3.5-11.7) years after phase 1 trial initiation for a particular therapy. 7 Recognizing these disparities, in 2017 the American Society of Clinical Oncology (ASCO)-Friends of Cancer Research HIV Working Group published guidelines for modernizing clinical trial eligibility criteria to include otherwise healthy PLWH. 7 Prior to this, the National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP) began efforts to promote inclusion of PLWH in clinical trials.
This culminated in changes to its formal protocol templates in September 2018, at which time clinical and laboratory criteria were recommended to investigators to identify patients with well-controlled HIV who were deemed unlikely to have HIV-related adverse outcomes precluding clinical trial participation. 8 However, the CTEP advocacy that resulted in this change evolved over time, and the utility of these efforts to promote inclusion of PLWH in ICB cancer clinical trials has not been assessed. We retrospectively reviewed CTEP-approved protocols for anti-PD1/PDL1 agents and compared HIV-specific eligibility criteria in the initially submitted letters of intent (LOIs) with criteria in the final approved protocols to evaluate the evolution in the inclusion of PLWH in anti-PD1/PDL1 ICB clinical trials that occurred concurrently with CTEP advocacy efforts during this time period.

Methods
This quality improvement study, including manuscript generation, was undertaken in concert with the Standards for Reporting Qualitative Research (SRQR) reporting guideline. 9 Per guidelines established by the Common Rule, this study was not submitted for institutional review board approval because it did not involve human participants and evaluated clinical trial eligibility criteria prior to any patient enrollment.
LOIs including anti-PD1/PDL1 agents nivolumab, pembrolizumab, atezolizumab, and durvalumab submitted to CTEP that preceded formal CTEP protocol template changes with final study approval between January 2014 and May 2019 were reviewed (eFigure in the Supplement).
LOIs approved for protocol development that proceeded to activated clinical trials within the study period were included. Studies designed specifically for PLWH were excluded. The frequency of inclusion of PLWH on initial LOI submission was compared with inclusion on final protocol following CTEP advocacy efforts. Advocacy efforts included requiring justification for exclusion of PLWH and formal discussion of inclusion criteria during conference calls between CTEP reviewers and trial

Statistical Analysis
Frequency of PLWH inclusion on submitted LOIs and final protocols was reported using summary statistics. Analyses of the association between calendar time and inclusion of PLWH (both in initial LOIs and approved protocols) were performed. Specifically, explicit inclusion of PLWH (yes vs no or not specified) was modeled as a function of calendar time (in years) using logistic regression. This was done separately for the inclusion of PLWH in initially submitted LOIs and approved protocols. All analyses are descriptive and hypothesis-generating. R statistical software version 3.

(R Project for
Statistical Computing) was used for statistical analyses from April to September 2020.
At the initial LOI stage, 14 of 87 proposals (16%) included PLWH ( Table 2 and   malignant neoplasm and CD4 cell count). One study mandated a CD4 cell count of greater than 200 cells/μL off all ART without evidence of opportunistic infection for 60 days prior to randomization.
Another study required that enrolled PLWH be under the care of an infectious disease specialist, otherwise a formal consult would be made.  Among the 25 protocols to exclude PLWH, 21 (84%) were earlier phase studies (pilot to phase 2) and 4 (16%) were later phase studies (phase 2/3 to phase 3). Only 13 of 25 protocols (52%) provided justification for exclusion of PLWH. Safety was the most commonly cited concern (9 of 13 studies), followed by efficacy in an immunocompromised individual (4 of 13 studies), and study drug-ART interaction (3 of 13 studies). One trial that excluded PLWH noted that HIV testing was not explicitly a criterion for inclusion in the study.
Logistic regression was used to assess the association between inclusion of PLWH in anti-PD1/ PDL1 cancer clinical trials and calendar time. Results of these analyses suggested an association between calendar time and LOI inclusion of PLWH (odds ratio, 3.38; 95% CI, 1.14-3.91) but not

Discussion
We evaluated the evolution of inclusion of PLWH in anti-PD1/PDL1 cancer clinical trials that occurred concurrent with CTEP advocacy efforts. Overall, inclusion of PLWH increased from 16% at the LOI stage to 70% at the final approved protocol stage of development following CTEP advocacy efforts.
Increases were observed irrespective of anti-PD1/PDL1 agent or study phase, and inclusion of PLWH on initially submitted LOIs appeared to increase over time.
Despite growing data demonstrating the safety of anti-PD1/PDL1 therapy in PLWH, such patients have routinely been excluded from ICB clinical trials. In our analysis, only 16% of proposals included PLWH at the LOI stage of development. Similarly, in a recent meta-analysis 10  and drug-drug interactions as rationale for exclusion of PLWH. This finding is not surprising, as the majority of trials to exclude PLWH in our study (84%) were earlier phase trials (pilot to phase 2), which primarily focus on safety, pharmacokinetics, pharmacodynamics, and early efficacy signals.
Evidence continues to emerge refuting these concerns. Retrospective analyses 13

Conclusions
This quality improvement study identified encouraging trends in inclusion of PLWH in anti-PD1/PDL1 cancer trials that occurred concurrent with CTEP advocacy. These findings suggest that advocacy efforts by CTEP and others may help to meaningfully broaden inclusion criteria for other patient populations underrepresented in cancer clinical trials (eg, organ dysfunction and chronic viral infections).